COMBINATION TREATMENT OF CD38-EXPRESSING TUMORS

1 . A method for inhibiting growth and/or proliferation of tumor cells expressing CD38 in an individual in need thereof, which method comprises administration to the said individual of

i) a non-agonistic antibody which binds to CD38,

ii) at least one corticosteroid, and

iii) at least one non-corticosteroid chemotherapeutic agent.

2 . A method for treating cancer involving tumor cells expressing CD38 in an individual in need thereof, which method comprises administration to the said individual of:

i) a non-agonistic antibody which binds to CD38,

ii) optionally at least one corticosteroid, and

iii) optionally at least one non-corticosteroid chemotherapeutic agent,

followed by autologous peripheral stem cell or bone marrow transplantation.

3 . The method of claim 1 , wherein said at least one non-corticosteroid chemotherapeutic agent comprises a cytotoxic agent, an angiogenesis inhibitor, an alkylating agent, a glutamic acid derivative, a proteasome inhibitor, a vinca alkaloid, and/or an anthracycline.

4 . (canceled)

5 . The method of claim 1 , wherein said at least one non-corticosteroid chemotherapeutic agent comprises one or more agents selected from the group consisting of: melphalan, mechlorethamine, thioepa, chlorambucil, carmustine (BSNU), lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, dacarbazine (DTIC), procarbazine, mitomycin C, cisplatin and other platinum derivatives, such as carboplatin.

6 . The method of claim 1 , wherein said at least one non-corticosteroid chemotherapeutic agent comprises a glutamic acid derivative, such as thalidomide (Thalomid®) or a thalidomide analog, e.g. CC 5013 (lenalidomide, Revlimid™) or CC4047 (Actimid™).

7 . The method of claim 1 , wherein said at least one non-corticosteroid chemotherapeutic agent comprises a proteasome inhibitor, such as bortezomib (Velcade®).

8 - 9 . (canceled)

10 . The method of claim 1 , wherein said at least one corticosteroid comprises a glucocorticoid.

11 . The method of claim 1 , wherein:

(a) said at least one corticosteroid comprises prednisone;

(b) said at least one corticosteroid comprises prednisone and said at least one non-corticosteroid chemotherapeutic agent comprises melphalan;

(c) said at least one corticosteroid comprises prednisone and said at least one non-corticosteroid chemotherapeutic agent comprises thalidomide;

(d) said at least one corticosteroid comprises prednisone and said at least one non-corticosteroid chemotherapeutic agent comprises melphalan and thalidomide;

(e) said at least one corticosteroid comprises dexamethasone;

(f) said at least one corticosteroid comprises dexamethasone and said at least one non-corticosteroid chemotherapeutic agent comprises thalidomide and/or lenalidomide; or

(g) said at least one corticosteroid comprises dexamethasone and said at least one non-corticosteroid chemotherapeutic agent comprises vincristine and/or doxorubicin.

12 - 17 . (canceled)

18 . The method of claim 1 , comprising the further administration of interferon-alpha.

19 . The method of claim 1 , wherein said antibody is a monoclonal antibody.

20 . The method of claim 1 , wherein said antibody is a human monoclonal antibody.

21 . (canceled)

22 . The method of claim 1 , wherein said antibody:

(a) does not induce release of significant IL-6 by human monocytes or peripheral blood mononuclear cells;

(b) does not induce release of detectable IFN-γ by human T cells or peripheral blood mononuclear cells;

(c) is internalized by CD38 expressing cells;

(d) induces ADCC;

(e) induces CDC in the presence of complement;

(f) inhibits the synthesis of cGDPR;

(g) inhibits the synthesis of cADPR; and/or

(h) binds to human CD38 with an affinity (KD) of below 10 −8 M.

23 - 31 . (canceled)

32 . The method of claim 1 , wherein said antibody comprises:

(a) a V H CDR3 having the sequence as set forth in SEQ ID No:10 or competes for CD38 binding with said antibody, e.g. by binding the same epitope as said antibody;

(b) a V H CDR3 having the sequence as set forth in SEQ ID No:20 or competes for CD38 binding with said antibody, e.g. by binding the same epitope as said antibody; or

(c) a V H CDR3 having the sequence as set forth in SEQ ID No:30 or competes for CD38 binding with said antibody, e.g. by binding the same epitope as said antibody.

33 . The method of claim 1 , wherein said antibody comprises:

(a) a V L CDR3 having the sequence as set forth in SEQ ID No:5 and a V H CDR3 having the sequence as set forth in SEQ ID No: 10;

(b) a V L CDR3 having the sequence as set forth in SEQ ID No: 15 and a V H CDR3 having the sequence as set forth in SEQ ID No:20; or

(c) a V L CDR3 having the sequence as set forth in SEQ ID No:25 and a V H CDR3 having the sequence as set forth in SEQ ID No:30.

34 . The method of claim 1 , wherein said antibody comprises human light chain and human heavy variable regions, wherein:

(a) the light chain variable region comprises a V L CDR1 having the sequence as set forth in SEQ ID No:3, a V L CDR2 having the sequence as set forth in SEQ ID No:4 and a V L CDR3 having the sequence as set forth in SEQ ID No:5, and the heavy chain variable region comprises a V H CDR 1 having the sequence as set forth in SEQ ID No:8, a V H CDR2 having the sequence as set forth in SEQ ID No:9 and a V H CDR3 having the sequence as set forth in SEQ ID No: 10;

(b) the light chain variable region comprises a V L CDR1 having the sequence as set forth in SEQ ID No:13, a V L CDR2 having the sequence as set forth in SEQ ID No: 14 and a V L CDR3 having the sequence as set forth in SEQ ID No: 15, and the heavy chain variable region comprises a V H CDR 1 having the sequence as set forth in SEQ ID No:18, a V H CDR2 having the sequence as set forth in SEQ ID No: 19 and a V H CDR3 having the sequence as set forth in SEQ ID No:20; or

(c) the light chain variable region comprises a V L CDR1 having the sequence as set forth in SEQ ID No:23, a V L CDR2 having the sequence as set forth in SEQ ID No:24 and a V L CDR3 having the sequence as set forth in SEQ ID No:25, and the heavy chain variable region comprises a V H CDR I having the sequence as set forth in SEQ ID No:28, a V H CDR2 having the sequence as set forth in SEQ ID No:29 and a V H CDR3 having the sequence as set forth in SEQ ID No:30.

35 . The method of claim 32 , wherein said antibody comprises:

(a) a V L region having the amino acid sequence as set forth in SEQ ID No:2 or a V L region having at least about 90%, such as at least about 95% amino acid sequence identity to the sequence as set forth in SEQ ID No:2;

(b) a V L region having the amino acid sequence as set forth in SEQ ID No: 12 or a V L region having at least about 90%, such as at least about 95% amino acid sequence identity to the sequence according to SEQ ID No: 12; or

(c) a V L region having the amino acid sequence as set forth in SEQ ID No:22 or a V L region having at least about 90%, such as at least about 95% amino acid sequence identity to the sequence according to SEQ ID No:22.

36 . The method of claim 32 , wherein said antibody comprises:

(a) a V H region having the amino acid sequence as set forth in SEQ ID No:7 or a V H region having at least about 90%, such as at least about 95% amino acid sequence identity to the sequence as set forth in SEQ ID No:7 or a V H region having 1-5, such as 1-3 amino acid substitutions, deletions or additions compared to the sequence as set forth in SEQ ID No:7;

(b) a V H region having the amino acid sequence as set forth in SEQ ID No: 17 or a V H region having at least about 90%, such as at least about 95% amino acid sequence identity to the sequence as set forth in SEQ ID No: 17 or a V H region having 1-5, such as 1-3 amino acid substitutions, deletions or additions compared to the sequence as set forth in SEQ ID No: 17; or

(c) a V H region having the amino acid sequence as set forth in SEQ ID No:27 or a V H region having at least about 90%, such as at least about 95% amino acid sequence identity to the sequence according to SEQ ID No:27 or a V H region having 1-5, such as 1-3 amino acid substitutions, deletions or additions compared to the sequence as set forth in SEQ ID No:27.

37 - 46 . (canceled)

47 . The method of claim 1 , wherein said antibody is a full length IgG1, IgG2, IgG3, IgG4, IgD, IgA, IgE, or IgM antibody, such as an IgG1 antibody, preferably an IgG1,κ antibody or an IgM antibody, preferably an IgM,κ antibody.

48 . The method of claim 1 , wherein said antibody is a human monoclonal antibody comprising

(i) a heavy chain variable region amino acid sequence derived from a human Hv1263/3M28 (V H I) germline sequence and a light chain variable region amino acid sequence derived from a human L15 (VκI) germline sequence; or

(ii) a heavy chain variable region amino acid sequence derived from a human V H 3-DP-47/V3-23 (V H III) germline sequence and a light chain variable region amino acid sequence derived from a human L6 (VκI) germline sequence.

49 . (canceled)

50 . The method of claim 1 , wherein said antibody is conjugated to a cytotoxic agent, a radioisotope, or a drug.

51 . The method of claim 1 , wherein said antibody is a bispecific or multispecific molecule and has a binding specificity for a human effector cell.

52 . (canceled)

53 . The method of claim 1 , wherein said tumor cells are multiple myeloma cells or chronic lymphocytic leukemia cells.

54 . The method of claim 1 , wherein said tumor cells are recurrent or refractory tumor cells.

55 - 56 . (canceled)

57 . The method of claim 1 , wherein said individual has:

(a) not undergone previous anti-cancer treatment for the same cancer;

(b) not responded to a previous anti-cancer treatment for the same cancer;

(c) previously undergone autologous peripheral stem cell or bone marrow transplantation;

and/or

(d) enrolled to undergo subsequent autologous peripheral stem cell or bone marrow transplantation.

58 - 60 . (canceled)

61 . The method of claim 1 , wherein the antibody, at least one corticosteroid and at least one non-corticosteroid chemotherapeutic agent are administered simultaneously.

62 . The method of claim 1 , wherein the antibody, at least one corticosteroid and at least one non-corticosteroid chemotherapeutic agent are administered sequentially.

63 . The method of claim 1 , wherein the antibody, at least one corticosteroid and at least one non-corticosteroid chemotherapeutic agent are all administered separately.

64 . The method of claim 1 , wherein the antibody, at least one corticosteroid and at least one non-corticosteroid chemotherapeutic agent are co-administered in one or two pharmaceutical compositions.

65 . The method of claim 62 , wherein the antibody is administered at least 1 day, such as at least 2 days, e.g. at least one week, before administration of said at least one corticosteroid and said at least one non-corticosteroid chemotherapeutic agent.

66 . The method of claim 1 , wherein the antibody is administered in a dose of 1 mg/kg or more, such as a dose of from 1 to 20 mg/kg, e.g. a dose of from 5 to 20 mg/kg, e.g. a dose of 8 mg/kg.

67 . The method of claim 1 , wherein the antibody is administered once weekly for 2 to 12 weeks, such as for 3 to 10 weeks, such as for 4 to 8 weeks.

68 . (canceled)

69 . The method of claim 2 , wherein the cancer is multiple myeloma or chronic lymphocytic leukemia.

70 - 71 . (canceled)

72 . A therapeutic combination for inhibiting growth and/or proliferation of tumor cells expressing CD38, comprising

i) a non-agonistic antibody which binds to CD38,

ii) at least one corticosteroid, and

iii) at least one non-corticosteroid chemotherapeutic agent,

wherein the combination is suitable for separate, sequential and/or simultaneous administration.

73 . (canceled)